Currently, tuberculosis (TB) ranks as the second leading cause of death from an infectious disease worldwide, after the human immunodeficiency virus (HIV). Mycobacterium tuberculosis, the bacterium responsible for causing TB, is unique due to its high content of mycolic acid in its lipid membrane, its slow replication time, and its ability to exploit the mammalian immune system. This bacterium divides slowly, replicating every eighteen to twenty hours, while other species of bacteria can replicate every thirty to sixty minutes. It can resist various disinfectants and can remain inactive for a period of weeks inside a macrophage, a type of cell that is part of the immune system which engulfs foreign harmful material as a defense mechanism. The bacterium has chemical defense systems that prevent it from being neutralized by the macrophage. M. tuberculosis transmits from person to person through the air via aerosol droplets containing the bacteria. TB typically infects the lungs, but can also infect other parts of the body. Individuals become contagious when the infection develops from latent to active, and can spread the disease to others by coughing, sneezing, or otherwise dispersing infected droplets through the air. About ninety percent of those infected have asymptomatic, latent TB infections (LTBI), with only a ten percent chance that the latent infection will progress to active TB. However, latent infections that progress to active infections kill more than fifty percent of patients if left untreated. Diagnosis of active TB relies on radiology (chest X-rays), as well as microscopic examination and microbiological culture of sputum or body fluids. Diagnosis of latent tuberculosis relies on the tuberculin skin test (TST) and/or blood tests that vary in complexity, cost and accuracy.
TB treatment requires at least four months of daily therapy with multiple drugs due to the poor efficacy of available antibiotics against different strains of M. tuberculosis bacilli. Drug-resistant tuberculosis is caused by M. tuberculosis organisms that are resistant to at least one front-line anti-tuberculosis drug. Improper administration and poor adherence by patients when using the two front-line anti-tuberculosis drugs, isoniazid and rifampin, have greatly contributed to the emergence of bacilli that have various levels of resistance to these drugs. This resistance often arises in areas with poor national infrastructure for dispensing and monitoring anti-tuberculosis drugs. Recent World Health Organization (WHO) global surveys have revealed that resistant strains of TB exist in every country examined and has become a significant health problem in areas of Sub-Saharan Africa, Russia, and Central and Southeast Asia. Among drug resistant M. tuberculosis isolates, resistance to isoniazid is the most commonly observed form. While the majority of the 2.3 billion people infected with TB worldwide harbor the latent form, a patient that develops an active infection with a drug-resistant TB strain can transmit these strains to other individuals. Increasing incidences of resistant TB infections and costly, inadequate treatment options pose a large barrier for controlling this disease.
Anti-tuberculosis drug resistance is a major public health problem that threatens progress achieved in TB care and control worldwide. Drug resistance arises due to multiple factors, one being improper use of antibiotics when treating drug-resistant tuberculosis such as administration of improper treatment regimens and failure to ensure that patients complete the entire course of treatment. Use of ineffective treatment regimens and difficulty in detecting antibiotic resistance amongst bacterial strains has also exacerbated the evolution of drug resistant M. tuberculosis strains. Multidrug resistant tuberculosis (MDR-TB) strains are resistant to the two frontline TB drugs isoniazid and rifampin. Treating drug resistant forms of TB can be complicated, with only a fifty percent cure rate for MDR-TB and further complications caused by toxicity of alternate drugs used. Second-line drugs are a recognized treatment for MDR-TB, but they can cause significant side effects such as ototoxicity. Approximately one out of five MDR-TB patients suffer from permanent hearing loss when given a second-line drug. The cost of the pharmaceutical regimen needed to treat MDR-TB can be, on average, one hundred times greater than active TB treatment regimens, with differing prices based on the economy of the country the case is located in, highlighting a critical component to the embodiment described in this technology. In addition to administration of more costly drugs, the complexity of drug resistant TB treatment should be managed by or in close consultation with an expert in the disease, increasing the cost and care for the patient.
Extensively drug resistant TB (XDR-TB) was first reported in 2006 in Italy. XDR-TB strains are resistant to isoniazid, rifampicin, and the second-line TB drugs fluoroquinolines and at least one of the injectable aminoglycosides. Between 2006 and 2009, there were isolated cases of TB that were not affected by all first and second-line TB drugs. In 2009, over a dozen patients in Iran were resistant to all TB drugs and were considered to have totally drug resistant TB (TDR-TB). Although not as rapidly as MDR-TB, incidence rates of XDR and TDR cases have been increasing worldwide. As different forms of drug resistant TB cases continue to increase, the pursuit for TB control is considerably threatened and cost of second-line drugs impacts their administration.
A person that has developed an active M. tuberculosis infection typically undergoes six months of directly observed treatment short-course (DOTS) using a combination of the frontline TB drugs isoniazid, rifampicin, pyrazinamide, and ethambutol. Each of the anti-tuberculosis drugs is more effective at different stages and/or aspects of the disease. For example, isoniazid is utilized in the early stages of treatment therapy; its bactericidal ability reduces the sputum bacterial count because it is primarily active against the bacterium growing aerobically in pulmonary cavities. Pyrazinamide is most active under specific chemical conditions (i.e. acidities), making it functional for inactivating the microbes inside caseous necrotic foci which explains the little benefit of administering pyrazinamide after the second month. Rifampicin inactivates microbes that metabolize slowly, and sterilizes the patient's sputum, as demonstrated in clinical trials.
A limiting factor for effectiveness in TB treatment regimens is the length of treatment which in turn impacts a patient's adherence, affecting progression of infection and can result in resistance to the antibiotics prescribed. The standard regimen for treating latent TB is six months of using only isoniazid, however there is an alternative combination therapy of isoniazid and rifampicin which lasts for a minimum of three months. MDR-TB cases can cause treatment to lengthen up to an additional eighteen months.
Medical and research communities have recognized that new strategies are needed for both drugs and vaccines to combat the global spread of TB and resistant strains of TB. New tuberculosis drugs in development include delaminid, levofloxacin, moxifloxacin, sutezolid, AZD-5847, and SQ109. Delaminid, SQ109, sutezolid and AZD-5847 are at various stages of being evaluated in clinical trials. The vaccine Bacille Calmette-Guerin (BCG) is widely used outside of the U.S. in higher TB burdened countries, but it is also erratic in terms of efficacy and protection lasts less than twenty years. Published reports evaluating BCG indicate its effectiveness ranging from zero to eighty percent. However, the BCG vaccine is beneficial in preventing more severe forms of TB in children such as TB meningitis. Over the past twenty years, developments in vaccines have paralleled developments in genetic based technologies. Currently, there are new tuberculosis vaccines in various levels of development and clinical trials such as MTBVAC (a live-attenuated M. tuberculosis based vaccine), MVA85A (a viral vector based vaccine), RUTI (based on fragmented M. tuberculosis cells) and Ad5Ag85A (an adenovirus based vaccine). Some TB vaccines have been described in the scientific literature for over a decade but have not been deemed a medical success against various forms of TB.
Bedaquiline, trade name Sirturo, is a diarylquinoline molecule used in the treatment of MDR-TB and has undergone various clinical trials to determine its safety, tolerability, efficacy and rate of resistance acquisition. In December of 2012, the United States Food and Drug Administration approved the new drug to treat adults with pulmonary MDR-TB. When compared to standard regimens, the incorporation of bedaquiline in TB treatment reduced the time to reach sputum culture negativity. The acquisition of drug resistance and the reduction of some adverse effects was lower when using bedaquiline in treatment regimens rather than using it as a single agent. Bedaquiline has been shown to be more effective at curing TB when compared to control groups. More deaths have occurred in bedaquiline recipient groups (11.4%) compared to placebo groups (<3%), but the cause of these deaths was inconclusive and further data must be obtained. The development of bedaquiline is significant because it was the first TB antibiotic approved for the pharmaceutical market in forty years, and it is particularly effective for treating MDR-TB cases.
A common research and development process of antibiotics and other medicines is to test different structural variations of an initial molecule that demonstrates some medicinal efficacy. A prominent example was the initial discovery of penicillin and its bactericidal properties which lead to the development of additional penicillins. Currently there are a number of penicillins that are used including penicillin G, penicillin O, penicillin V, methicillin and amoxicillin that are produced either by microbes or semi-synthesis. Another example of this type of molecular restructuring resulted with the low-cost development of a new class of semisynthetic anti-mycobacterial drugs called spectinamides, which comprises of over one hundred and fifty analogs derived from the antibiotic spectinomycin. Prior to this development, spectinomycin was not utilized as a treatment for TB due to efflux of the drug. However, with structural modification to the drug, the Rv1258c efflux pump can be avoided and binding to the mycobacterial ribosome can increase. The mechanism of action is described as a protein synthesis inhibitor that binds to the 30S ribosome. Spectinamides have shown to have safe pharmacological activity, significantly reduce MIC values, and have activity against MDR-TB and XDR-TB strains. Despite significant work with this group of molecules, none have been introduced to the pharmaceutical market as an anti-tuberculosis drug.
Research and development of new vaccines and new drugs often has extensive time scales and costs involved in the development process. During this process, many drugs are not used to treat patients on a non-trial basis due to medical complications and/or efficacy problems encountered during development.
The pharmaceutical administration method of a drug must not only be effective, but also be able to be utilized by the population in need. The United States Food and Drug Administration defines over one hundred methods of administering the drug to the patient, which includes but is not limited to: auricular (otic), buccal, conjunctival, cutaneous, dental, electro-osmosis, endocervical, endosinusial, endotracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-arterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavernous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronal, dental, intracoronary, intracorporus, cavernosum, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric, occlusive dressing technique, ophthalmic, oral, oropharyngeal, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, and vaginal. Many TB patients reside in undeveloped regions and have minimal access to resources available in developed countries which limits the types of pharmaceutical administration methods that can be applied. Currently, many drugs are administered in these conditions using either oral (pill) or intramuscular injection (needle). Intramuscular injected anti-tuberculosis drugs, such as the second-line drugs amikacin and capreomycin, are not ideal forms of treatment due to discomfort for patients and increased care and costs for administration. The embodiment of this work describes a drug administered orally as a pill. To clarify, the form in which a medication is given to a patient (i.e. orally, intramuscular injection) is referred to as drug delivery or administration of the drug. When a molecular level platform such as a micelle, liposome, protein, nanoparticle, aggregate, etc. is used to carry a pharmaceutical agent in vivo or in vitro, it may also be referred to as a drug delivery agent or vehicle but it is at a different stage of administration.
Isoniazid was first described in the scientific literature in 1952. Since then, it has served as a primary antibiotic for reducing the effects of M. tuberculosis and has been a standard TB drug for decades. Isoniazid is a prodrug meaning the molecular structure changes upon entering the body. Isoniazid has several mechanisms that contribute to its medicinal activity and side effects including coupling with the NAD+/NADP+ intermediate species pair, acting to inhibit the unique cell wall lipid synthesis of the bacterium which utilizes mycolic acid, inhibiting nucleic acid synthesis, and decreasing respiration. Isoniazid resistant bacterial strains started being recognized by the medical community in the mid-1950's.
As a group, rifamycins were first identified in 1957 and were later used to treat tuberculosis patients, reducing the duration of treatment from eighteen to nine months. Within this group, rifampin is the most prescribed rifamycin to treat TB. A key structural characteristic of the TB drugs in the rifamycin group is the aromatic structure linked by aliphatic structures giving a relatively nonpolar structure allowing for easy diffusion across the nonpolar M. tuberculosis cell membrane, which has a high content of mycolic acid. This anti-tubercular drug group inhibits transcription by complexing a bacterial DNA-dependent RNA polymerase. Development of bacterial resistance to the rifamycin group was first recognized in 1970.
Pyrazinamide was first identified in 1952 and has both bacteriostatic and bactericidal properties. Incorporation of pyrazinamide into TB treatment regimens has reduced treatment length from nine to twelve months to the current six month regimen. Pyrazinamide does not have the same medical efficacy as isoniazid or rifampin, but does have a unique ability to affect dormant populations of M. tuberculosis in acidic environments.
Another front-line TB drug that has been used for decades is ethambutol which was first reported to be used against M. tuberculosis in 1961. Along with isoniazid, rifampin and pyrazinamide, it is part of the current treatment regimen for TB and works to kill actively replicating bacterium. Three years after its discovery, the first ethambutol resistant bacterial strain was recorded.
Streptomycin, first isolated in 1943, is another front-line antibiotic used to treat patients with TB and belongs to an antimicrobial group called aminoglycosides, which were the first group used to treat TB. Streptomycin may cause side effects including fetal auditory toxicity, neuromuscular paralysis, ototoxcity and nephrotoxicity. Streptomycin bacterial resistance was first recorded in 1950.
These five drugs are defined by the World Health Organization (WHO), a highly influential organization responsible for instilling international treatment recommendations, as Group I TB drugs and compose the standard regimen for treating active TB infections. There are a total of five groups (I, II, III, IV, V) of TB drugs listed by WHO. The Group I TB antibiotics, also called the front-line TB antibiotics, may induce side effects such as allergic reactions, unusual weakness or fatigue, nausea, vomiting, loss of appetite, abdominal pain, neuropathy, seizures, blurred vision, rashes, joint pain, hepatotoxicity, nephrotoxicity, and/or abnormal behavior.
Other TB drugs recognized by WHO include the Group II molecules amikacin, kanamycin, capreomycin, viomycin, and enviomycin; the Group III molecules ciprofloxacin, levofloxacin, and moxifloxacin; the Group IV molecules ethionamide, prothionamide, cycloserine; and the Group V molecules terizidone, rifabutin, clarithromycin, linezolid, thioacetazone, thioridazine, arginine, vitamin D, and bedaquiline. These groupings are used to help determine the type of TB to be treated (i.e. Groups II, III, IV are used to treat different forms of drug resistant TB) as well as effectiveness, cost and side effects. Group V drugs are considered the final choice when other options are not effective. All of these antibiotics contain functional groups (i.e. amines, amides) that can competitively form a strong bond with a cation such as copper (II) and copper (I). Given that all of these molecules have multiple nitrogen and/or oxygen atoms as part of their structures, they qualify as polarity adaptive molecules, which is an important parameter for the embodiment outlined in this disclosure.
Second-line TB drugs that have been evaluated using the delivery system described in this technology are capreomycin and amikacin. Capreomycin, first identified in the early 1960's, is water-soluble and administered intramuscularly via a painful injection. This second-line drug has severe side effects such as ototoxicity, nitrogen retention, electrolyte imbalance, and nephrotoxicity. Capreomycin is more expensive and is only used when front-line drugs are ineffective, in order to treat MDR-TB in combination with other anti-tuberculosis drugs. Amikacin, belonging to the aminoglycoside antibiotic group, is a second-line antibiotic used to treat MDR-TB. Amikacin binds to the 16s rRNA in the 30S small ribosomal subunit, inhibiting protein synthesis. Like capreomycin, amikacin is becoming utilized more often in the treatment of TB due to the increase of MDR-TB cases. Published studies have demonstrated that enclosing the antibiotic in a solid lipid nanoparticle reduced the amount of amikacin needed in TB treatments by half.
Macrophages are a part of the human immune system formed when the body recognizes an infection or when there is an increase in dying or dead cells. Macrophages are a specific type of white blood cell that captures and digests microbes, cancer cells, and other cellular particles that are not protected by a specific protein. Macrophages are large, often measuring more than ten micrometers in diameter and are produced by differentiation of monocytes, groups of white blood cells. When an infection is recognized, the monocytes move from the blood stream to the site of the infection, which is often the lung in M. tuberculosis infections. Once in the organ cellular changes occur to the white blood cell, which are unique to the type and location of the infection, as it transforms into a specialized macrophage. These specialized cells can survive for months at a time. Macrophages serve as the host for M. tuberculosis to replicate after a process called phagocytosis, or engulfing, the microbe. M. tuberculosis then uses the host to remain dormant until progressing into an active infection. The membrane of M. tuberculosis, which has high levels of mycolic acid, is presumed to provide protection from a range of internal processes inside the macrophage aimed at destroying the bacterium.
Chemical species can cross a cell membrane in a number of well-known physiological processes such as (1) phagocytosis, a process in which large structures such as bacteria and particles are engulfed (2) pinocystosis, a process in which the fluid phase is taken into the cell by the formation of a small vesicles by the cell membrane (3) macropinocytosis in which large fluid pockets that are greater than one micrometer in size are trapped (4) clathrin-mediated endocytosis which involves the formation of coated pits using cytosolic proteins in the membrane allowing cells to absorb molecules and (5) caveolae-mediated endocytosis in which molecules up to sixty nanometers in diameter are facilitated through the membrane starting with the formation of a membrane dimple. All of these processes are energy dependent and sucrose, which is one component of the drug delivery system described in this embodiment, has been shown to both accelerate and inhibit different endocytosis processes, an idea that supports the basis of this technology.
Applying the principles and advantages of nanotechnology to a drug delivery vehicle can provide the potential to deliver drugs to specific cells using different nanostructures. Drug delivery vehicles focus on maximizing bioavailability at specific locations in the body and for longer periods of time. This can potentially be achieved with molecular targeting by nano-engineered devices. The primary goals of nano-biotechnologies in drug delivery include: increased specificity in drug targeting and delivery, reduction in toxicity while maintaining therapeutic effects, greater safety and biocompatibility, and faster development of safe medicines. Due to the small sizes, nanostructures exhibit unique physicochemical and biological properties (e.g., an enhanced reactive area as well as an ability to cross cell and tissue barriers) making them a favorable material for biomedical applications and a growing area of novel research.
Other drug delivery vehicle approaches including micelles, liposomes, dendrimers and proteins have been involved in a large number of preliminary studies, but few candidates have been advanced through clinical trials for antibiotics. Many of these compounds have no direct medicinal effect or activity but serve to increase residence time in blood, thereby increasing exposure of the pharmaceutical agent to the disease. For example, poly-lactide-co-glycolide (PLG) nanoparticles have been used as drug delivery agents for rifampin, isoniazid, pyrazinamide and ethambutol against M. tuberculosis and have been shown to produce increased bioavailability and improved pharmacodynamics activity. The Alginate nanoparticle, a biodegradable composite, has been used to deliver rifampin, isoniazid, pyrazinamide and ethambutol to treat patients with M. tuberculosis infections and has demonstrated to have a high drug payload, improved pharmacokinetic activity and high therapeutic efficacy in clinical studies. A liposome system composed of hydrogenated soy phosphatidylcholine, cholesterol, and distearoylphosphatidylglycerol (DSPG) have been used to deliver the second-line TB drug amikacin against gram-negative bacteria and has shown to have prolonged drug exposure. In another published report, a lipid nanoparticle composed of stearic acid has been used to deliver rifampicin, isoniazid, and pyrazinamide to treat patients with M. tuberculosis and has demonstrated increased residence time, increased drug bioavailability, and decreased administration frequency.
An example of a dendrimer used to deliver an antibiotic is polyamidoamine (PAMAM) dendrimers which have been used to deliver the antibiotics nadifloxacin and prulifloxacin against various types of bacterial infections and has demonstrated increased water solubility, an important parameter due to the aqueous nature of blood. Another example of a nano-dendrimer system is the glycosylated polyacrylate nanoparticle which has been utilized to deliver the Beta-lactam ciprofloxacin against the bacterium Staphylococcus aureus and Bacillus anthracis, and demonstrated improved bioavailability and higher therapeutic efficacy. All of the drug delivery systems mentioned thus far do not provide an increase in the medicinal efficacy of the drug but are chemically inert and serve to make the drug more available at the diseased or infected site. The new technology described in this disclosure is a molecular method of drug delivery composed of three components bonded together with one or more anti-tuberculosis antibiotics and enclosed with a polymer to increase efficacy of the drug.
Liposomes, which are composite structures made of phospholipids that may contain small amounts of other molecules, are one of the most common molecular based vehicles used for targeted drug delivery. Liposomes can vary in size from nanometers to tens of micrometers. Unilamellar liposomes are smaller in size, with various targeting ligands attached to their surface, allowing for surface-attachment and accumulation in diseased areas. One issue in using liposomes is the immediate uptake and clearance by certain physiological systems when used in vivo and low stability when used in vitro. To overcome this problem, different forms of polyethylene glycol (PEG) are added to liposomes which can increase circulation time up to five fold. Another type of drug delivery vehicle used is polymeric micelles. Polymeric micelles are nanoscopic core/shell structures formed by amphiphilic block copolymers.
To understand the relevance of this invention and subsequent disclosure, it is important to review previous revealed intellectual property disclosures to recognize developments in the field. There are several drug delivery designs at the molecular level such as liposomes, polymeric micelles, lipoproteins, dendrimers, nanoparticles, and albumin. Typical parameters for a molecular level drug delivery vehicle include biodegradability, no toxicity, biocompatibility, and inability to be detected by immune mechanisms. Most of the well-recognized delivery systems are significantly larger and heavier than the medicinal agent they are transporting. Two unique aspects to the formulation disclosed in this application are (a) two of the delivery components used (i.e. copper(II), sucrose) are similar in size to the active ingredients (TB drugs) they help deliver and (b) the delivery components can impact biochemical cycles by serving as nutrients to improve efficacy of the drug and each can be toxic in another cellular biochemical cycle. Using examples below, novel developments in drug delivery involves platforms that are inert from a pharmaceutical perspective.
U.S. Pat. No. 8,394,839 B2, entitled “Rationally improved isoniazid and ethionamide derivatives and activity through selective isotopic substitutions” describes the use of exchanging the carbon-12 isotope, which has a natural abundance of 98.9%, with carbon-13 isotopes, which has a natural abundance of 1.1%. This disclosure revealed that the anti-tuberculosis drugs isoniazid and ethionamide could have improved medical efficacy against mycobacterial diseases using this isotope based technology.
U.S. Pat. No. 8,449,916 B1 entitled “Antimicrobial compositions and methods” describes treating and killing microbial infections in animals. This technology focuses on the use of polyanhydride microparticles, defined by diameters of at least one micrometer, and nanoparticles, defined by diameters between one and nine hundred and ninety nine nanometers. The particles defined contain a microbial agent that will slowly dissolve and release the pharmaceutical agent to treat the infection.
Patent EP 18774226 B1 (from WO2006117240A2) describes a method of inhibiting the activation of latent or active M. tuberculosis using a nucleic acid encoding an Mtb72f fusion protein. The invention also claims to shorten the drug regimen administration time scale for TB. The patient, which is described as a mammal, must have been previously immunized by the BCG vaccine.
U.S. Pat. No. 8,597,616 B2 entitled “Dry Powder drug delivery formulations, methods of use, and devices therefore” describes a new technology related to the use of a dry powder to deliver a pharmaceutical formulation for pulmonary applications. While the invention outlines the use of the delivery methods for patients with TB, it may also deliver therapeutic agents to treat exposure to nerve agents and toxic gas.
WO 2011016043 A2 also published as U.S. Pat. No. 8,951,563 entitled “Antibiotic drug delivery and potentiation” describes the use of a cochleate-based delivery system. The cochleate system, which can have a positive charge as great as +10, is composed of residues of amino acids and an amino-fatty acid moiety.
U.S. Pat. No. 6,455,073 B1 entitled “Covalent microparticle-drug conjugates for biological targeting” describes a novel method to deliver antiviral, antimicrobial and antibiotic drugs to cells with phagocytic capabilities. The active ingredients in the microparticles include isoniazid, rifampin, capreomycin, ethionamide, amikacin, and cycloserine. The preparation involves a number of serivazation and synthetic routes such as the synthesis of a carbamate derivatized polymer coating, as well as several processes that involve the release of the drug such as urease catalyzed release from polymer-coated microparticles.
U.S. Pat. No. 8,110,181 B2 describes a method that uses an aerosol generator to deliver interferons. Alpha, beta, and gamma interferons are one active component of the aerosol. The aerosol delivery of the interferons is for the treatment of pulmonary diseases. The interferon is combined with some antibiotic agents and delivered in doses between ten and one thousand milligrams.
U.S. Pat. No. 8,697,653 B2 entitled “Microparticle formulation for pulmonary drug delivery of anti-infective molecule for treatment of infectious diseases” describes an inhalable microparticle coupled with a biodegradable lipid that can be used as a delivery system for the treatment of pulmonary TB, MDR-TB, Methicillin-resistant Staphylococcus aureus (MRSA) pneumonias and Methicillin-sensitive Staphylococcus aureus (MSSA) pneumonias by delivering the recommended amount of the pharmaceutical agent to the patient.
There are currently no drug delivery agents or drug boosters improving efficacy on a molecular level that are used to deliver TB antibiotics that have been approved by the United States Food and Drug Administration or are approved by multinational agencies that recommend TB treatment regimens such as the World Health Organization.
This invention focuses on the composition of a tablet with a drug delivery platform that, when administered in vivo or in vitro, consists of an existing antibiotic, a saccharide, a transition metal cation and a polymer to increase the efficacy of the drug by impacting physiological processes. Additional species are included in the tablet to help with other facets of tablet composition, rigidity, dissolution and ingestion. When developing a drug delivery agent, the toxicity, pharmacodynamics, pharmacokinetics and medical efficacy of each component should be considered.
Polyethylene glycol (PEG-3350) has approval for use in the pharmaceutical industry by the Food and Drug Administration. Brand names that PEG are sold under include clenz-lyte, co-lav, colovage, colyte, colyte with flavor packs, e-z-em prep lyte, glycolax, glycoprep, go-evac, golytely, halflytely, lax-lyte with flavor packs, miralax, mircera, moviprep, nulytely, nulytely-flavored, PEG 3350 and electrolytes, PEG-lyte, suclear, and trilyte. The general mechanism of action for PEG is the osmotic effect causing water to be retained in the digestive tract and results with liquefaction of feces. The pharmacodynamics induce a liquid stool which cleans the lower gastrointestinal tract within four to six hours. Pharmacokinetic data for pure PEG indicates that as the polymer gets larger, it absorbs through the intestinal tract at a lower rate.
As described in the peer reviewed scientific literature, maximum PEG-3350 plasma concentrations occur at approximately three hours after a single dose, and a non-detectable level is reached eighteen hours after administration. Less than one percent of the polymer is excreted in urine while over ninety percent is excreted in fecal matter. In this embodiment, the role of PEG is to form an aggregate and provide a carrier through the gastrointestinal tract, trapping the transition metal cation-saccharide-antibiotic complex and allowing it to cross the membrane to the serum. PEG can be administered by intravenous, oral, rectal, and topical routes and is found in household products such as toothpaste, shampoo, moisturizers, and some foods. It has been demonstrated that PEG not only forms aggregates in a physiological environment, but also that macrophages will ingest these foreign and loosely formed nanoparticles because they are not recognized. By itself, PEG-3350 has no useful pharmaceutical activity against M. tuberculosis. 
The process of PEGylation has dramatically increased the use of PEG in the drug delivery field. PEGylation involves attaching molecules of various sizes and uses to the polymer, potentially providing a number of improvements or advantages including increased drug stability, increased residence time in the body or serum, increased drug solubility in water or serum, protection from hydrogen bonding to unwanted species (applied Lipinski's Rule of Five), protection from acid catalyzed reactions, and reduced degradation due to enzymes. Preliminary ADME (absorption, distribution, metabolism, and excretion) studies for PEGylated compounds indicated the functionalized species containing PEG have improved values compared to the pure compounds. There are a number of PEGylated compounds available in the pharmaceutical market now including: Naloxegol (Movantik), Peginesatide (Omontys), Pegloticase (Krystexxa), Certolizumab pegol (Cimzia), Methoxy polyethylene glycol-epoetin beta (Mircera), Pegaptanib (Macugen), Pegfilgrastim (Neulasta), Pegvisomant (Somavert), Peginterferon alfa-2a (Pegasys), Doxorubicin HCl liposome (Doxil/Caelyx), Peginterferon alfa (Peglntron), Pegaspargase (Oncaspar), and Pegademase bovine (Adagen).
The disaccharide sucrose is utilized as an inert ingredient in syrups, gums, chewable tablets, and lozenges. Excess sucrose consumption can be correlated with dental cavities, diabetes and weight gain. Sucrose is found in a number of available drugs including; Acetaminophen and Hydrocodone Bitartrate, Adipex, Amphetamine and Dextroamphetamine Extended Release, Cymbalta, Dexamethasone, Levothyroxine Sodium, Lortab, Methylphenidate Hydrochloride, Metoprolol Succinate, Norco, Omeprazole, Phendimetrazine Tartrate and Phentermine Hydrochloride. A saccharide such as sucrose incorporated into the drug delivery system outlined in this embodiment serves as one of the components acting as a nutrient increasing uptake of the drug attached and inducing one or more physiological processes within the target to increase efficacy of the drug.
Another consideration in this embodiment is the incorporation of a transition metal cation such as copper, a copper salt, zinc, a zinc salt, iron, an iron salt, nickel or a nickel salt as a carrier. All of these metals are essential nutrients in the body at low levels but can cause toxicity at higher concentrations. The toxicity level can vary depending on whether the cation is administered as a free ion (i.e. copper (II)(aq), nickel(II)(aq)) or bound to a species such as a protein or a small molecule. For example, copper gluconate or copper citrate are two examples of copper complexes used for treating copper deficiency, a rare disorder that occurs from a lack of zinc in diets, intestinal bypass surgery, and Menkes disease. Copper is an important nutrient that is found in a number of enzymes (2-furoyl-CoA dehydrogenase, Amine oxidase, Bilirubin oxidase, Catechol oxidase, etc.) and proteins (cytochrome c oxidase, hemocyanin, tyrosinase, amicyanin, plastocyanin and pseudoazurin). A healthy adult has approximately two parts per million copper in their body, but over ninety-nine percent of this copper is utilized by and incorporated in enzymes and proteins. Adding a transition metal ion such as copper to the drug delivery system outlined in this embodiment serves as one of the components acting as a nutrient increasing uptake of the drug attached, inducing one or more physiological processes within the target to increase efficacy of the drug, increasing the structural stability of the drug, and/or serving independently as a biocide.
The quantities of each component of the drug delivery system including the existing anti-tuberculosis drug that may be used are given as an example, but are not to be construed to be in any way limiting for the present invention. Using the front-line anti-tuberculosis drug isoniazid as an example, the quantities of the additional components and antibiotic of the drug delivery system are given as a 1:1:1:1 ratio and are as follows: 10 milligrams of isoniazid, 24.96 milligrams of sucrose, 12.408 milligrams of copper (II) chloride dihydrate, and 244.52 milligrams of PEG-3350. Additional examples of quantities for this technology are given later in this disclosure.